Coronavirus disease 2019 (COVID-19) contagiousness is critical in the healthcare setting, and it varies along with severity of disease, immunosuppression of host, and medication. Reference Cogliati Dezza, Oliva and Cancelli1 In severe cases of COVID-19, viral replication and transmission have been described up to 20 days after the onset of symptoms, sometimes longer in immunocompromised patients. Reference Van Kampen, Van de Vijver and Fraaij2,Reference Hawken, Sellers and Smedberg3 Still, the Centers for Disease Control and Prevention (CDC) guidelines recommend removal from isolation 21 days after the onset of symptoms, after resolution of fever and improvement of symptoms. A test-based strategy “can be considered.” 4
In the province of Quebec, Canada, a single dose of tocilizumab along with 10 days of dexamethasone are recommended in severe cases of COVID-19. Considering the relative immunosuppression induced by those drugs Reference Giles, Hutchinson and Sonnemann5,Reference Sebba6 and the fact that they are used in severe cases, uncertainty regarding the optimal duration of isolation surfaced. One study showed that tocilizumab and dexamethasone treatments were independently associated with prolonged shedding of viral RNA. Reference Cogliati Dezza, Oliva and Cancelli1
We can assess contagiousness and viral replication through viral culture. Reference Jefferson, Spencer, Brassey and Heneghan7 Unfortunately, this method takes time and specialized laboratories. Alternatively, we can evaluate viral shedding and extrapolate contagiousness through cycle threshold (Ct) values of nucleic acid amplification tests (NAATs) of SARS-CoV-2 RNA. Reference Jefferson, Spencer, Brassey and Heneghan7
We describe 10 patients who received tocilizumab and dexamethasone for severe COVID-19 due to the α (alpha) variant (B.1.1.7). We correlated clinical state, Ct values of NAAT, and viral culture results to suggest safe discontinuation of isolation measures.
Methods
Patient selection
We reviewed cases of severe COVID-19 that occurred in our institution from March 23 through April 21, 2021. We included every patient who received tocilizumab and dexamethasone for whom isolation duration was evaluated by an infectious disease (ID) consultant. We reviewed comorbidities, symptomatology and temperature, isolation duration, and NAAT results, and viral culture results.
Setting
The Centre Hospitalier Universitaire de Québec-Université Laval is a 1,660-bed, acute-care university institution in Quebec City, Canada. The COVID-19 patients are hospitalized on COVID-19–specific units with dedicated staff for their isolation duration, then they are transferred to non–COVID-19 wards. The COVID-19 units comprise ∼115 beds and 15 ICU beds in 2 separate sites.
Diagnostic tests
The decision to obtain NAAT or viral culture was delegated to the ID consultant. All specimens were obtained through nasopharyngeal swabs. NAAT were conducted on Simplexa assay (DiaSorin Molecular), targeting genes S and ORF1ab. Viral cultures were done on Vero E6 cells in a Biosafety level 3 laboratory, using a previously described method. Reference Longtin, Charest and Quach8 After a year-long pause (as a biosafety mitigation measure), viral cultures were allowed again in our institution in March 2021, if prescribed by an ID specialist to evaluate patients post tocilizumab and dexamethasone. Our case series includes every viral culture performed within the study period.
Infection control
According to local guidelines, patients presenting with severe illness (defined as intensive care warranting high-flow oxygen or mechanical ventilation) could be removed from isolation after 21 days if they had been apyretic for 48 hours and clinically improving for 24 hours. Isolation duration could be extended by ID specialists, when called upon. As a clinical surrogate for our patients’ contagiousness, we monitored new COVID-19 cases in healthcare workers and other patients on non–COVID-19 wards after removal from isolation.
Results
Patients aged 46–75 years who had a severe case of COVID-19 (α variant) and received a single dose of tocilizumab along with dexamethasone for 10 days were included in this study. They all needed invasive ventilation for a period ranging from 5 days to >1 month. They did not receive any other COVID-19–specific treatment. Every patient but one recovered.
Overall, there is a discrepancy between our results (Table 1) and approved guidelines concerning duration of isolation for severe COVID-19. At day 21 after onset of symptoms, 7 of 10 patients remained in isolation, mostly because of lack of clinical improvement, low Ct values, and, in 2 cases, positive viral cultures.
Patient Characteristics, Comorbidities, Date of Onset of Symptoms, Intubation, Results of NAAT and Viral Cultures and Isolation Duration
Note. NAAT, nucleic acid amplification test; M, male; F, female; HTN, arterial hypertension; UTI, urinary tract infection; OOS, onset of symptoms; ND, not detected.
No secondary COVID-19 infection on non–COVID-19 wards were identified when isolation measures were lifted.
Discussion
Our case series advocates against the deisolation of severely ill COVID-19 patients who receive tocilizumab and dexamethasone based on clinical improvement alone at day 21. Of 10 patients, 5 had Ct values <30, and 2 patients had a positive viral culture after day 20, which contrasts with previous data. 4,Reference Jefferson, Spencer, Brassey and Heneghan7 The use of tocilizumab and dexamethasone in our case series may have contributed to a prolonged viral shedding, along with severe infection. More research is needed to determine the underlying causes and risk factors of prolonged infectivity.
Our research reflects what is currently known on the correlation between high NAAT Ct values and negative culture, past a certain threshold. Ct values may vary with the technology used—5 studies reported no growth on viral culture on specimen with Ct values ranging from > 24 to >35. Reference Jefferson, Spencer, Brassey and Heneghan7 Because the Simplexa assay does not require molecular extraction, Ct values can be somewhat lower than with other methods (−2.1 cycles compared to the CDC diagnostic panel). Reference Lieberman, Pepper, Naccache, Huang, Jerome and Greninger9
Ct values fluctuated substantially over multiple days samplings, which might represent variable shedding linked to specimen quality or volume and severity of disease. Reference Hawken, Sellers and Smedberg3 Patients with prolonged positive testing (>28 days) have also been shown to be the ones in whom Ct values fluctuate the most, Reference Hawken, Sellers and Smedberg3 which was the case for patient 3, notably.
For severe COVID-19 cases after tocilizumab and dexamethasone, our data advocates for a deisolation strategy based on 2 separate NAAT results (thus mitigating the fluctuation of Ct values); a conservative Ct cutoff value >30 could be used in clinically improving patients at least 21 days after symptoms onset. In our case series, Ct values >30 in clinically improving patients correlated with negative viral culture (and presumed absence of contagiousness Reference Jefferson, Spencer, Brassey and Heneghan7 ). After lifting isolation, no secondary infection was attributed to our patients. It is possible (but unlikely) that they were still contagious but did not infect others due to infection prevention and control measures. Conversely, the fact that some patients have a prolonged viral excretion might explain some of the nosocomial outbreaks seen during the pandemic.
The principal strength of this case series is that we have presented viral culture results, whereas while most previous studies have shown RNA viral shedding through NAAT alone. Providing detailed case summaries might also be of use to clinicians. Finally, to our knowledge, few other studies have addressed the impact of tocilizumab and dexamethasone on isolation duration.
The principal limitation of our case series was its small sample size, which precludes strong conclusions and generalization. Nonetheless, our patients’ age and comorbidities reflect COVID-19 ICU population. All patients presented with the α (alpha) variant, the most prevalent variant at the time in our province. Notably, due to clinicians’ autonomy and laboratory workers’ unavailability on weekends, cultures could not be systematically obtained at day 21. Reflecting real-life situations, our case series was conducted without a control group.
Relying on NAAT results in addition to clinical criteria is the safest option in our opinion, considering positive viral culture obtained in a clinically improved patient. Additionally, using NAAT as an objective surrogate for contagiousness probably constitutes the best option in view of newer variables: vaccination status, breakthrough infections, and variants of concern, especially o (omicron) and δ (delta) variants. The δ variant has been associated with longer duration of Ct values <30. Reference Ong, Chiew and Ang10 Larger trials are needed to confirm our data and to explore its applicability in those situations.
Acknowledgments
Financial support
No financial support was provided relevant to this article.
Conflicts of interest
All authors report no conflicts of interest relevant to this article.
